There is a rapid growth in the number of people living with Alzheimer?s disease, and only 25% get diagnosed; still we do not know its etiology or have effective treatments. To examine factors which contribute to switching from normal to pathological aging we focus on the APOE polymorphic alleles. The causes for increased risk, or conversely resilience, conferred by the major APOE alleles are not known. The APOE4/4 genotype is the main genetic risk for late onset Alzheimer?s disease (AD), and is associated with a 30-55% risk of developing mild cognitive impairment or AD by age 85, compared to 10-15% for the APOE3/3 genotype. In contrast APOE2 is under-represented in AD patients, and it has been associated with longevity. To help understand the mechanisms through which APOE genes and their products differentially modulate the brain and its circuits to switch from healthy to pathological aging, we will take an integrative and unbiased multi-disciplinary approach using homozygous targeted replacement APOE2, APOE3, and APOE4 mice expressing the major human APOE isoforms, under the control of the mouse endogenous ApoE promoter. APOE2 mice have a significantly longer lifespan than APOE3 mice, which in turn have a significantly longer lifespan than APOE4 mice. These mice reasonably match the human APOE-genotype/lifespan data. To model the human immune response to aging we will use double-transgenic mice that express human NOS2 gene products. This modification enables nitric oxide (NO) production and immune activity regulated by NO to better mimic the human response. Our models include male and female APOE2/HN (APOE2/2 + human NOS2 on a mouse Nos2-/- background), APOE3/HN, and APOE4/HN mice, at 2 ages corresponding to middle and old human age. Mice will be characterized with a cognitive behavioral battery, and with MRI to determine selective vulnerability of brain networks. Our imaging measures will be based on volume, vascular perfusion, and diffusion tensor imaging; and will provide connectomes and network measures. RNA-Seq transcriptomics will identify differential expression of gene products associated with APOE genotypes, during aging. We will use an unbiased statistical approach to map molecular pathways underlying the behavioral and imaging phenotypes for aging. Our efforts will help build models that explain the influence of APOE genotypes on age and AD associated network vulnerability. We expect to hone in on pathways involved in aging, AD, inflammation, and oxidative phosphorylation. To test models, we will add a stressor conferring risk in aging and AD, through a high fat/high sugar diet (mimicking the Western diet). We will assess behavioral, and MRI phenotypes, in conjunction with transcriptomics, and determine through pathway analysis how diet shifts the predicted outcomes in male and female APOE2/HN, APOE3/HN and APOE4/HN mice. Our research will reveal mechanisms through which APOE interacts with environmental stressors to confer vulnerability, or resilience to select brain circuits during aging.